Type I, or insulin-dependent, diabetes mellitus (also referred to herein as DM-I) is known to occur spontaneously in humans, rats and mice. There is a genetic susceptibility to DM-I associated with certain haplotypes of Class II antigens of the major histocompatability complex (MHC). The pathology of DM-I consists of the progressive inflammatory infiltration of pancreatic islets (i.e., insulitis) containing immunocytes targeted specifically to insulin-secreting β-cells. This pathology develops over an indeterminate period of time (months to years).
DM-I is a chronic disease that requires life-long treatment to prevent acute illness and to reduce the risk of long-term complications. Restrictive diets and daily insulin injections can be burdensome for patients, thus reducing compliance, and even with treatment complications such as cataracts, retinopathy, glaucoma, renal disease and circulatory disease are prevalent.
Systemic lupus erythematosus (SLE), is a chronic, inflammatory autoimmune disease characterized by the production of autoantibodies having specificity for a wide range of self-antigens. SLE autoantibodies mediate organ damage by directly binding to host tissues and by forming immune complexes that deposit in vascular tissues and activate immune cells. Organs targeted in SLE include the skin, kidneys, vasculature, joints, various blood elements, and the central nervous system (CNS). The severity of disease, the spectrum of clinical involvement, and the response to therapy vary widely among patients. This clinical heterogeneity makes it challenging to diagnose and manage lupus.
CD93 is expressed by endothelial cells, cells of myeloid lineage, platelets and early hematopoeitic stem cells, and is a lineage specific marker of early B cell developmental stages. Normally, CD93 is expressed at high levels on Pro-, Pre- and immature BM B cell progenitors, as well as, TR B cells in the periphery (FIG. 1). The CD93 gene is located at 84 cM on murine chromosome 2 and encodes a type I O-glycosylated transmembrane protein whose domain structure includes an amino-terminal C-type lectin domain, a tandem array of five EGF-like repeats, a single hydrophobic trans-membrane region, and a short cytoplasmic domain that contains a PDZ binding domain and a moesin interaction site. This domain structure bears a unique resemblance to the selectin-family of adhesion molecules. Additionally, the CD93 is subject to metalloprotease mediated ectodomain cleavage, or shedding, which is characteristic of several inflammatory mediators and adhesion molecules including TNF-α, TGF-α, TGF-β, EGF, CD44 and L-selectin. Despite its initial identification as a receptor for the C1q component of complement and demonstration of an in vivo kinetic defect in the clearance of apoptotic cells in CD93−/− mice, the in vivo function of the molecule is yet to be elucidated.